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      Apoptosis in subicular neurons: A comparison between suicide and Addison's disease

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          Abstract

          Background:

          Stress and depression shows possible links to neuronal death in hippocampus. Subiculum plays a prominent role in limbic stress integration and direct effect of corticosteroids on subicular neurons needs to be defined to assess its subsequent impact on hippocampal plasticity.

          Aim:

          This study was intended to assess apoptosis in subicular neurons of a young depressed suicide victim, where presumably stress induced excess of corticosteroids and a case of young Addison's disease with low level of corticosteroids.

          Materials and Method:

          Both bilateral adrenal glands (Addison's) and subiculum (both cases) were initially stained with hematoxylin and eosin; subicular neurons of both cases were examined for the degree of apoptosis using ‘ApopTag Kit’. Apoptotic cell counts were expressed as average number of labeled cells/mm 2 and the results were analysed statistically using a non-parametric Mann–Whitney U test.

          Result:

          Apoptotic neurons were detected in the subicular region of both suicide and Addison victims, and it is statistically significant in both right and left between the cases ( P < 0.05). In suicide victim, the neuronal apoptosis is considerably significant between the two hemispheres ( P < 0.05), in contrast to Addison disease where the number of neuronal cell death between right and left was statistically insignificant ( P > 0.05).

          Conclusion:

          The present study confirms the vulnerability of the subicular neurons to apoptosis, possibly due to corticosteroids in both ends of spectrum.

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          Most cited references16

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          The impact of pesticide regulations on suicide in Sri Lanka.

          Between 1950 and 1995 suicide rates in Sri Lanka increased 8-fold to a peak of 47 per 100,000 in 1995. By 2005, rates had halved. We investigated whether Sri Lanka's regulatory controls on the import and sale of pesticides that are particularly toxic to humans were responsible for these changes in the incidence of suicide. Ecological analysis using graphical and descriptive approaches to identify time trends in suicide and risk factors for suicide in Sri Lanka, 1975-2005. Restrictions on the import and sales of WHO Class I toxicity pesticides in 1995 and endosulfan in 1998, coincided with reductions in suicide in both men and women of all ages. 19,769 fewer suicides occurred in 1996-2005 as compared with 1986-95. Secular trends in unemployment, alcohol misuse, divorce, pesticide use and the years associated with Sri Lanka's Civil war did not appear to be associated with these declines. These data indicate that in countries where pesticides are commonly used in acts of self-poisoning, import controls on the most toxic pesticides may have a favourable impact on suicide. In Asia, there are an estimated 300,000 deaths from pesticide self-poisoning annually. National and international policies restricting the sale of pesticides that are most toxic to humans may have a major impact on suicides in the region.
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            Role of the ventral subiculum in stress integration.

            The mammalian subiculum plays a prominent role in inhibition of the hypothalamo-pituitary-adrenocortical (HPA) axis. Lesion and stimulation studies indicate that the hippocampus, acting via output neurons of the ventral subiculum, acts to attenuate stress-induced glucocorticoid release. Lesions of the ventral subiculum enhance glucocorticoid secretion following psychogenic, but not systemic stressors, indicating that the influence of this structure on the HPA system is stressor-specific. Anatomical analyses fail to demonstrate direct interactions of the subiculum with principal stress-effector neurons in the paraventricular hypothalamus, consistent with a trans-synaptic mechanism of action. Accordingly, tracing data indicate that glutamatergic ventral subiculum neurons innervate GABAergic neurons in several paraventricular nucleus-projecting neurons in the hypothalamus and basal forebrain, suggesting that inhibition is mediated by glutamate-GABA relays. The subiculum also innervates several limbic forebrain structures that in turn have bisynaptic projections to paraventricular neurons, such as the prefrontal cortex, amygdala and lateral septum, suggesting that the subiculum may have a generalized up-stream influence on limbic stress integration. Finally, recent information suggests that the subiculum may also be stress excitatory under some circumstances, and that there may be substantial strain or individual differences in the net contribution of the subiculum, to stress integration. Overall, the present state of knowledge indicates that the role of the subiculum in stress integration is complex, and likely involves interactions of stress-relevant subicular output with limbic-hypothalamic stress-integrative circuits.
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              Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation.

              An important question arising from previous observations in vivo is whether glucocorticoids can directly influence neuronal survival in the hippocampus. To this end, a primary postnatal hippocampal culture system containing mature neurons and expressing both glucocorticoid (GR) and mineralocorticoid (MR) receptors was developed. Results show that the GR agonist dexamethasone (DEX) targets neurons (microtubule-associated protein 2-positive cells) for death through apoptosis. GR-mediated cell death was counteracted by the MR agonist aldosterone (ALDO). Antagonism of MR with spironolactone ([7alpha-(acetylthio)-3-oxo-17alpha-pregn-4-ene-21 carbolactone] (SPIRO)) causes a dose-dependent increase in neuronal apoptosis in the absence of DEX, indicating that nanomolar levels of corticosterone present in the culture medium, which are sufficient to activate MR, can mask the apoptotic response to DEX. Indeed, both SPIRO and another MR antagonist, oxprenoate potassium ((7alpha,17alpha)-17-hydroxy-3-oxo-7-propylpregn-4-ene-21-carboxylic acid, potassium salt (RU28318)), accentuated DEX-induced apoptosis. These results demonstrate that GRs can act directly to induce hippocampal neuronal death and that demonstration of their full apoptotic potency depends on abolition of survival-promoting actions mediated by MR.
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                Author and article information

                Journal
                Indian J Psychiatry
                IJPsy
                Indian Journal of Psychiatry
                Medknow Publications (India )
                0019-5545
                1998-3794
                Oct-Dec 2009
                : 51
                : 4
                : 276-279
                Affiliations
                Genetic Diagnostic and Research Laboratory, Department of Anatomy, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, Sri Lanka
                [1 ]Department of Forensic Medicine, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, Sri Lanka
                [2 ]Department of Pathology, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, Sri Lanka
                [3 ]Department of Pharmacology, College of Medicine, Seoul National University, Seoul, South Korea
                Author notes
                Address for correspondence: Dr. K. Ranil D. De Silva, Genetic Diagnostic and Research Laboratory, Department of Anatomy, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, Sri Lanka. E-mail: ranilds@ 123456sltnet.lk / ranil@ 123456sjp.ac.lk
                Article
                IJPsy-51-276
                10.4103/0019-5545.58293
                2802375
                20048453
                3717c048-0f96-4cca-bf29-61a896431333
                © Indian Journal of Psychiatry

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Categories
                Original Article

                Clinical Psychology & Psychiatry
                corticosteroids,apoptosis,subiculum,suicide,addison disease
                Clinical Psychology & Psychiatry
                corticosteroids, apoptosis, subiculum, suicide, addison disease

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